More Gene Mutations Linked to Autism Risk

Combination of Inherited and New Genetic Mutations Acting Together

PHILADELPHIA – More pieces in the complex autism inheritance puzzle are emerging in the latest study from a research team including geneticists from the University of Pennsylvania School of Medicine, The Children’s Hospital of Philadelphia (CHOP), and several collaborating institutions. This study identified 27 different genetic regions where rare copy number variations – missing or extra copies of DNA segments – were found in the genes of children with autism spectrum disorders (ASDs), but not in the healthy controls. The complex combination of missing or extra copies of certain genes is thought to interfere with gene function, which can disrupt the production of proteins necessary for normal neurological development.

“We are finding that both inherited and new, or de novo, genetic mutations are scattered throughout the genome and it is becoming clear that different combinations of these variations contribute to autism susceptibility,” said study author Maja Bucan, PhD, Professor of Genetics at the University of Pennsylvania School of Medicine and the Chair of the Steering committee for Autism Speaks’ Autism Genetic Resource Exchange (AGRE). “We are grateful to families of children with autism spectrum disorders for their willingness to participate in genetic studies because family-based studies have many advantages. We have learned a lot both from genetic analyses of children with autism as well as the analyses of their parents and their unaffected siblings.”

Researchers compared genetic samples of 3832 individuals from 912 families with multiple autistic children from the AGRE cohort against genetic samples of 1070 disease free children from the Children’s Hospital of Philadelphia. This study also uncovered two novel genes where variations were found, BZRAP1 and MDGA2 – thought to be important in synaptic function and neurological development, respectively. Interestingly, key variants on these genes were passed down in some, but not all, of the affected individuals in families.

“We focused on changes in the exons of DNA—protein-coding areas in which deletions or duplications are more likely to directly disrupt biological functions,” said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia and associate professor of Pediatrics at the University of Pennsylvania School of Medicine. “We identified additional autism susceptibility genes, many of which, as we previously found, belong to the neuronal cell adhesion molecule family involved in the development of brain circuitry in early childhood.” He added that the team discovered many “private” gene mutations, those found only in one or a few individuals or families—an indication of genetic complexity, in which many different gene changes may contribute to an autism spectrum disorder.

The findings were published in the June 26 edition of the journal PLoS Genetics.

By further refining the genetic landscape of ASDs, the current study expands the findings of two large autism gene studies published in April, led by Hakonarson and Gerard Schellenberg, Ph.D., professor of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine, as well as Bucan and others. One study was the first to report common gene variants in ASDs. The other identified copy number variants that raise the risk of having an ASD. Both studies found gene changes on two biological pathways with crucial roles in early central nervous system development. Hakonarson and Bucan said the latest findings reinforce the view that multiple gene variants, both common and rare, may be interacting to cause the heterogeneous group of disorders included under autism spectrum disorders.

The Autism Genetic Resource Exchange (AGRE), a program of Autism Speaks, provided genetic biomaterials and clinical data from families that have more than one family member diagnosed with an Autism Spectrum Disorder. Blood samples donated by children and their families at CHOP were used as healthy controls. AGRE makes data publicly available to qualified researchers worldwide.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.

About Autism Speaks
Autism Speaks is the nation's largest autism science and advocacy organization, dedicated to funding research into the causes, prevention, treatments and a cure for autism; increasing awareness of autism spectrum disorders; and advocating for the needs of individuals with autism and their families. Autism Speaks funds more than $30 million each year in new autism research, in addition to supporting the Autism Treatment Network, Autism Genetic Resource Exchange, Autism Clinical Trials Network, Autism Tissue Program and a range of other scientific and medical programs.